Document xjmXyLbb3qbrYGzaV1OrLNmRb

British Journal of Industrial Medicine 1987;44:1124-128 Leukaemia in benzene workers: a retrospective cohort study S-N YIN,' G-L LI,' F-D TAIN,1 Z-I FU,1 C JIN,1 Y-J CHEN,2 S-J LUO,3 P-Z YE,4 J-Z ZHANG,5 G-C WANG,6 X-C ZHANG,7 H-N WU,8 Q-C ZHONG9 From the Institute ofHealth,' Chinese Academy of Preventive Medicine, Beiing, Stationsfor Health and Prevention ofInfection ofShanghai,2 Sichuan,3 Tianjin,6 and Nanchang,8 and Institutesfor Prevention and Treatment of Occupational Disease in Heilong]iang,4 Shenyang,5 Helan,7 and Guangzhou,9 China ABSTRACT A retrospective cohort study was conducted in 233 benzene factories and 83 control factories in 12 cities in China. The benzene cohort and the control cohort consisted of 28460 benzene exposed workers (178 556 person-years in 1972-8 1) and 28257 control workers (199 201 person-years). Thirty cases of leukaemia (25 dead and 5 alive) were detected in the former and four cases (all dead) in the latter. The leukaemia mortality rate was 14/100 000 person-years in the benzene cohort and 2/100000 person-years in the control cohort; the standardized mortality ratio was 5 74 (p < 0 01 by U test). The average latency of benzene leukaemia was 114 years. Most (76-6%) cases of benzene leukaemia were of the acute type. The mortality due to benzene leukaemia was high in organic synthesis plants followed by painting and rubber synthesis industries. The concentration of benzene to which patients with a leukaemia were exposed ranged from 10 to 1000 mg/m3 (mostly from 50 to 500 mg/m3). Of the 25 cases of leukaemia, seven had a history of chronic benzene poisoning before the leukaemia developed. In addition to its presence in the general environment as a pollutant benzene is still used in various industries and in China some 500 000 workers are exposed to benzene or a benzene containing mixture (SN Yin et al, reported at scientific committee on maximum permissible limits meeting, London, 1983). The aetiological relation between exposure to benzene and leukaemia has been reported by several authors including Vigliani and Saita,' Ishimaru et al,2 Aksoy,3 and Rinsky et al.4 Whereas the leukaemogenic property of benzene in man has been well established,5 the epidemiological data are still considered insufficient and, especially, there has been no epidemiological report on benzene leukaemia in China. To study the causal relation between benzene and leukaemia a further retrospective cohort study was undertaken in 1982-3. The present paper reports the major findings of the study. The relation of other malignancies to exposure to benzene will be described in a separate report.6 Materials and methods Tianjin, Chengdu, Chongqing, Haerbin, Shenyang, Jinzhou, Zhengzhou, Luoyang, Guangzhou, Nan- chang, and Kaifeng, China, in 1982-3. The members of the benzene group were selected from 233 painting, shoe-making, rubber synthesis, leather, and adhesive and organic synthesis factories in the 12 cities cited. The subjects had worked in those factories for at least half a year between 1 January 1972 and 31 December 1981. Those in the control cohort were from 83 machine production, textile, and cloth factories in which there were no known exposures to benzene or other occupational carcinogens. The sex and age distribution in the control group were similar to that of the benzene group. The controls had also worked in the same cities for at least half a year during the same period. The drop out rate was 0-8% in the benzene cohort and 1-3% in the control cohort. Thus the ben- zene cohort consisted of 28 460 workers (15 643 men, 12 817 women) and the control cohort of 28 257 subjects (16 621 men, 12 336 women). Both cohorts were followed up from 1972 to 1981 so that 178 556 person-years were obtained for the benzene cohort The study was conducted in the cities of Shanghai, and 199 201 the control cohort. Items investigated included the occupational his- Accepted 13 May 1986 tory of the individuals, a history of benzene poisoning 124 Leukaemia in benzene workers Table 1 Mortality and relative risk ofleukaemia Benzene Controls Sex Person-years Death Mortality Person-years Death Men Women 100025 78531 17 8 7-00 122268 5 3 10 19 77932 5 1 Total 178556 25 1400 199201-0 4 *RR = Relative risk defined as the ratio of mortality B to mortality C. Table 2 Standardised mortality ratio (observed/expected) for benzene leukaemia Mortality 2-47 1-28 2-01 Sex Men Women Total Deaths Observed 17 8 25 Expected 3-392 0-964 4-356 SMR 5-01 8-30 5-74 Table 3 Mortality rate ofleukaemia in various industries Industry Workers Painting Paint producing Rubber Glueing Shoemaking Leather Organic synthesis Miscellaneous 13604 4533 2208 1512 3811 323 1976 493 Total 28460 *Mortality rate: unit, 1/100 000 person-years. Person-years 87935-5 26859 13544 11082 23117 1795 12037 2685-5 178556 Leukaemia 14 2 2 1 1 5 - 25 125 RR* p 6-88 <0-01 724 <005 6-97 <0-01 Up 3 30 <0-01 2-49 < 0 05 4 13 <0 01 Mortality* 15 9 7-4 14-8 90 4-3 41-5 14 0 and other specific disease, death certificates (for all known deaths), working conditions, and atmospheric benzene concentrations in the workplace; this information was collected from factory records. Benzene concentrations were determined by means of grab samples followed in the main by gas chromatographic analyses. The cases of leukaemia, aplastic anaemia, and benzene poisoning were obtained from hospital records; the diagnosis of benzene poisoning was established based on China national criteria for diagnosis of benzene poisoning' including occupational history, a peripheral leukocyte count of less than 4000 cells/mm3, and symptoms or signs in the central ner- vous system. The vital status was followed up until 31 December 1981. The standardized mortality ratio (SMR) was calculated with reference to the deaths in the control cohort. Results MORTALITY AND RELATIVE RISK OF LEUKAEMIA In total, 30 cases of benzene leukaemia were found in the benzene cohort, of whom 25 had died and five were alive in 1972-81; four cases of leukaemia were found in the control cohort (all dead). The mortality rate of leukaemia was 14/100000 person-years in the benzene cohort and 2-01/100000 person-years in the control cohort. The relative risk of leukaemia for the benzene workers was 6-97 and was significantly high both in men and women (table 1). As 25 cases of benzene leukaemia (excluding five live cases) were observed compared with 4-3 expected, the SMR was 5-01 for men, 8-30 for women, or 5 74 for both (table 2). When the mortality due to benzene leukaemia was compared in the various industries, the rate was highest in organic synthesis factories followed by the painting and rubber synthesis industries (table 3). AGE AND LATENCY IN CASES OF LEUKAEMIA The ages of the patients with leukaemia in the benzene cohort ranged from 24 to 62 with a mean of 39.7 years (38-1 for men, 36 0 for women). The mean age of the patients with leukaemia was lower in the ben- 126 Yin, Li, Tain, Fu, Jin, Chen, Luo, Ye, Zhang, Wang, Zhang, Wu, Zhong 200- LtI100- 301 28 20 % 810_ s10 10 1!i 25 30 35 40 45 50 i55 60 65 70 Age ( years ) Fig I Leukaemia mortality rate in male workers at various ages. Solid line indicates mortality rate among workers in benzene cohort. Broken line indicates values among male adults in big cities in China (data obtainedftom the National Control Office ofthe Ministry ofHealth, 1979). zene cohort (38-1 years when both sexes combined) than in the control cohort (46-7 years). The mortality for leukaemia increased in the age range 35-45 in the benzene cohort (fig 1). The average age of the workers when exposure began was 27-8 years. Figure 2 shows the relation between the start of exposure and the time of diagnosis (the latency period). Among the 30 cases of leukaemia in the benzene cohort the average latency was 11-4 years (minimum 0-8, maximum 49 5 years, respectively). The cumulative mortality of leukaemia was in proportion to the duration of exposure up to 20 years and then levelled off (fig 3), as go-" 04- 0- 00-N 800-; In- , 10 15 20 25 30 3 40 45 50 55 60 Age (years) Fig 2 Age at start ofexposure, ofdiagnosis ofleukaemia, and latency of30 cases ofleukaemia. 0 indicates ages ofthe initiation ofthe exposure and 1'f ages at which diagnosis of leukaemia was established. Connecting lines show period of latency. .E* 120 x 110 E c 100 o*_>z-0CI1 90. P8Eo 80 0..... x0/ x 0- a_ C -) 50,.1%0 0 5 10 15 20 25 30 35 Duration of exposure (years) Fig 3 Relation ofcumulative mortality ofleukaemia with duration ofexposure. Crosses indicate cumulative mortality ofleukaemia observed. Open circles indicate value estimated by an orthogonal polynomical curve of y = 55-56 + 4 4471 x - 009248x2 where y is cumulative mortality (l/105 persons) and x is duration ofbenzene exposure (years). was well described by an orthogonal polynominal curve of the form: y = 55 56 + 4-4471 x - 0-09248x2 where y is the cumulative mortality (1/105 persons) and x is the duration of benzene exposure (years). Table 4 Benzene concentration in workplaces where cases ofleukaemia were observed No ofcases Industry I Laboratory in rubber factory 2 Chemical reagent 3 Paint 4 Glue 5 Paint 6 Paint 7 Paint 8 Paint 9 Paint 10 Paint 11 Paint 12 Benzene refined 13 Chemical analysis 14 Paint 1 5 Cleaning 16 Organic synthesis 17 Paint 18 Shoemaking 19 Paint 20 Paint 21 Paint 22 Paint 23 Paint 24 Paint producing 25 Paint 26 Paint 27 Organic synthesis 28 Paint 29 Rubber 30 Paint producing *Single measurement. Benzene concentration (mg/m3) 136 2(99-3-173-1) 253 9 (20-440 2) 50 2(0-220) 100(30-150) 190-6(5-1200) 26-5(0-250) 15 5(3-39-4) 15(10-20) 203-1(25-500) 2393 (0-4736) 30-2(0-341 3) 4742 (0-4024) 87-8(5-3-170 2) 1104 7 (3-5-3826)* 6-5(16-1114) 15 4(1 4-50-0) 243-6(0-618) 13.3* 190 8(42-453) 468-1(13 7-5508) 301(250-352) 1189(31-3-2064) 575-2(2 2-6102) 21 4(0 7-80-1) 96-8 68-2(54-7-138 8) 8-3 (6 5-10)* 37 1(2-1-94 1) 86-4 (4 9-116-2) 159 5(10-733) Leukaemia in benzene workers BENZENE CONCENTRATION IN THE WORKPLACES WHERE CASES OF LEUKAEMIA WERE OBSERVED Table 4 shows the benzene concentrations in the workplaces where the 30 patients with leukaemia had worked. The mean concentrations varied in a wide range of 10 to 1000 mg/m3 but were mostly in the range 50-500mg/m3. LEUKAEMIA MORTALITY AMONG CASES OF BENZENE POISONING In the benzene cohort 196 cases of chronic benzene poisoning and aplastic anaemia were found; seven of the 25 patients with leukaemia had a history of chronic benzene poisoning (for criteria of the diagnosis, see materials and methods) or aplastic anaemia, or both, before being diagnosed as having a leukaemia. The leukaemia mortality among benzene poisoning cases was 700-70/100000 person-years, and was 49 times higher than that in the benzene workers (14/100000). TYPES OF BENZENE LEUKAEMIA Among the 30 cases of benzene leukaemia, 23 (76 7%) were acute and seven (23.3%) chronic. The cases of acute leukaemia comprised 13 myelogenous, four monocytic, two myelocytic-monocytic, one erythromyelocytic, and three lymphocytic leukaemia. Chronic leukaemia included five with myelogenous leukaemia, one lymphosarcomatous leukaemia, and one unidentified case. Discussion Benzene is a well established human carcinogen.' In addition, Goldstein et al and Maltoni etal have presented data suggesting that benzene may cause leukaemia in rodents.8 9 About 289 benzene exposure related cases of leukaemia have been reported in Italy, China, France, Japan, the Soviet Union, Turkey, and the United States.'0 In the past 20 years several epidemiological studies have shown that long term occupational exposure to benzene at high concentration is associated with the occurrence of various blood dyscasias including leukaemia.'" For example, Aksoy reported 34 cases of leukaemia among shoemakers in Istanbul in 1967-753; the incidence of leukaemia was 13/100000 in shoemakers by contrast with 6/100000 in the general population. Rinksy etal investigated two pliofilm manufacturing plants and found that the SMR for benzene leukaemia was 560.' In a recent study of a chemical plant where benzene had been used as a material for organic synthesis DeCoufle etal observed four deaths due to lymphoreticular cancers (2 leukaemia, 1 leukaemia multiple 127 myeloma, 1 multiple myeloma) in a 30 year follow up study of 259 male workers by contrast with 1 1 expected deaths12; no quantitative data on benzene exposure were available, however. Arp et al reviewed the history of solvent use, raw materials specification, and the job description of 15 cases of lymphatic leukaemia in a rubber industry and comparing them with 30 matched controls found that patients with leukaemia had spent more time in jobs with potential exposure to coal tar based benzene and xylene. 3 Tsai et al by contrast found no deaths from leukaemia in a study of 454 workers who had been employed in a refinery from 1952 to 1978 and exposed to benzene either at 0-14ppm (median; refinery workers) or 0 53 ppm (median; workers in benzene related units)."4 In the present retrospective cohort study of workers exposed to benzene the mortality from leukaemia was higher than that in the control cohort (SMR 574 for men + women; 501 for men, 830 for women) being in line with the findings by Rinsky etal.4 The mean latency period of benzene leukaemia was I1 -4 years (range 0 8 to 49 5) (fig 2). It is similar to the observation by Vigliani and Saita of 1-46 years,' Goguel etal of 1-20 years,'5 and Infante et al of 2-21 years.16 The average age of initial exposure to benzene among the cases of leukaemia was 27-8 years. When 11 4 years of latency is added the sum is about 39 years, which falls in the age range (35-45) of peak leukaemia mortality (fig 1). This may explain why the leukaemia mortality was highest in those aged 35-45. With regard to the benzene concentration to which patients with leukaemia were exposed, some authors have estimated that it ranged from 200 to 600 ppm without exact details.17 18 Recently, Rinsky etal reported that their patients were exposed to benzene at 16-100ppm, only slightly over the current OSHA standard of 1Oppm.4 In the present study the benzene concentrations in the workplaces where the patients had worked were reported to be 10-IOOmg/m3 (about 3-300 ppm) and mostly in the range 50-500mg/m3 (about 16-160 ppm), the levels being similar to the observation by Rinsky et al.4 There remains a possibility that leukaemia may develop among the less heavily exposed workers. In fact in the present study three cases of leukaemia were associated with a benzene concentration of 10 mg/m3 in the workplace air even though the occupational hygiene data were not adequate for quantitative estimation of exposure intensity. In this connection Infante etal20 cited the fact that Kligerman et al (paper presented at the international symposium on sister chromatid exchange, Brookhaven, 1984) had detected a significant increase in sister chromatid exchanges (SCE) in peripheral lymphocytes and in the micronuclei in bone marrow erythrocytes of mice exposed 128 Yin, Li, Tain, Fu, Jin, Chen, Luo, Ye, Zhang, Wang, Zhang, Wu, Zhong to benzene at 1Oppm for only 10 hours. By contrast, Sarto et al found no significant increase in SCE in the blood of the workers exposed to benzene in the range of 0-2 to 12-4 pm, although changes in chromosomal aberration were significant.20 Thus this possibility apparently deserves further attention. It should be noted that seven of the 25 patients had had a history of chronic benzene poisoning such as leukopaenia or aplastic anaemia, or both, before the leukaemia developed. The leukaemia mortality was as high as 700.70/100000 person-years in cases of chronic benzene poisoning. Aksoy also observed the development of 13 cases of leukaemia in 51 pancytopaenic patients with benzene exposure.2' Thus a close relation between leukaemia and benzene poisoning should be considered. Accordingly, it may be deduced that the prevention of benzene poisoning, is the best way to prevent benzene leukaemia. The way to monitor preleukaemic changes in benzene poisoning, however, remains to be established. This investigation was supported and organised by the Ministry of Public Health of the Government of China. We are grateful to Professor M Ikeda, Department of Environmental Health, Tohoku University School of Medicine, Sendai, Japan, for his interest in this work and his critical review of the manuscript. We thank S-X Yand, Y-Z Wang, W-Y Zhang, T-R Dai, X-J Chao, F-Y Jie, Y-H Huan, D-Y Ding, Z-L Jiang, C-Q Wu, J-S Zhou, and J-F Mu for participating in this study. Requests for reprints to: Dr Songnian Yin, Institute of Health, Chinese Academy of Preventive Medicine, 29 Nan Wei Road, Beijing, China. References I Vigliani EC, Saita G. Benzene and leukaemia. N Engl J Med 1964;271:872-6. 2 Ishimaru T, Okada H, Tomiyasu T, Tsuchimoto T, Hoshino T. Tchimaru M. Occupational factors in the epidemiology of leukaemia in Hiroshima and Nagasaki. Am J Epidemiol 1971;93:157-65. 3 Aksoy M. Different types of malignancies due to occupational exposure to benzene. A review of recent observation in Turkey. Environ Res 1980;23:181-90. 4 Rinsky RA, Young RJ, Smith AB. Leukaemia in benzene workers. Am J Ind Med 1981;2:217-45. 5 International Agency for Research on Cancer. Monographs on the evaluation of the carcinogenic risk of chemicals to humans. Vol 29. Benzene. Lyon: IARC, 1982:93-148. 6 Yin S-N, Li G-L, Tain F-D, et al. Epidemiological study on relationship between benzene and leukaemia and other cancer. Chinese Journal of Industry Hygiene Occupational Disease (in press). 7 China national criteria for diagnosis ofbenzene poisoning. Beijing: Ministry of Public Health of the Government of China, 1974. (In Chinese.) 8 Goldstein BD, Snyder CA, Laskin S, Bromberg I, Albert RE, Nelson N. Myelogenous leukaemia in rodents inhaling benzene. Toxicol Lett 1982;13:169-73. 9 Maltoni C, Conti B, Cotti G, et al. Experimental studies on benzene carcinogenicity at the Bologna Institute of Oncology. Am J Ind Med 1985;7:415-46. 10 Yin S-N, Li G-L. Advance of studies on benzene leukaemia. Communication of Medical Research 1981;11:5-7. (In Chinese.) 11 Van Raalte HGS, Grasso P. Hematological, myelotoxic, clastoxic, carcinogenic and leukemogenic effects of benzene. Regulatory Toxicology and Pharmacology 1982;2:153-76. 12 Decoufle P, Blattner WA, Blair A. Mortality among chemical workers exposed to benzene and other agents. Environ Res 1983;30:16-25. 13 Arp EW, Wolf PW, Checkoway H. Lymphocytic leukaemia and exposures to benzene and other solvents in the rubber industry. J Occup Med 1983;25:598-602. 14 Tsai SP, Wen CP, Weiss NS, Wong 0, McClellan WA, Gibson RL. Retrospective surveillance studies of workers in benzene areas of refineries. J Occup Med 1983;25:685-92. 15 Goguel A, Gavigneaux A, Bernard J. Les leucemics benzeniques de la region Parisienne entre 1950 et 1965 (etude de 50 observations). Nouv Rev Fr Hematol 1967;7:465-80. 16 Infante PF, Rinsky PA, Wagoner JK, Young RJ. Leukemia in benzene workers. Lancet 1977;ii:76-8. 17 Aksoy M, Dincol K, Erdem S, Dincol G. Acute leukemia due to chronic exposure to benzene. Am J Med 1972;52:160-6. 18 Vigliani EC. Leukaemia associated with benzene exposure. Ann NY Acad Sci 1976;271:143-51. 19 Infante PF, White MC. Projections of leukaemia risk associated with occupational exposure to benzene. Am J Ind Med 1985;7:403-1 3. 20 Sarto F, Cominato I, Pinton AM, et al. A cytogenetic study on workers exposed to low concentrations of benzene. Carcino- genesis 1984;5:827-32. 21 Aksoy M. Malignancies due to occupational exposure to benzene. Am J Ind Med 1985;7:395-402.